Masataka Nishimura

Sodium sensitivity and cardiovascular events in patients with essential hypertension

BACKGROUND In patients with sodium-sensitive hypertension, glomerular pressure is increased and microalbuminuria, a marker of glomerular hypertension, is a predictor of cardiovascular events. Similarly, the lack of a nocturnal decrease in blood pressure in these patients is also associated with an increased risk of cardiovascular events. We hypothesised that sodium sensitivity may be the common factor and carried out a retrospective study of cardiovascular events in patients with essential hypertension who had had sodium sensitivity measured in our clinic. METHODS Sodium sensitivity was assessed in about 350 patients with essential hypertension during the initial investigation of their disorder. The definition of sodium sensitivity was a 10% or greater difference in blood pressure on low-sodium or high-sodium diets. By alphabetical order, the records of 201 patients were obtained and 156 patients without pre-existing disorders were followed up. The records of patients who had a cardiovascular event or died were reviewed without knowledge of the patients sodium-sensitivity status. FINDINGS 62 patients were deemed sodium sensitive and 94 non-sodium sensitive. Left-ventricular hypertrophy was found more frequently in the sodium-sensitive group than in the non-sodium-sensitive group (38 vs 16%; p < 0.01), whereas significantly fewer patients in this group smoked (23 vs 42%; p < 0.05). There were 17 cardiovascular events in the sodium-sensitive group and 14 in the non-sodium-sensitive group. The rate of total, non-fatal and fatal cardiovascular events, was 2.0 per 100 patient-years in the non-sodium-sensitive group and 4.3 per 100 patient-years in the sodium-sensitive group. Coxs proportional-hazards model identified sodium sensitivity (p < 0.01), mean arterial pressure (p < 0.01), and smoking (p < 0.01) as independent cardiovascular risk factors. INTERPRETATION Cardiovascular events occurred more frequently in patients with sodium-sensitive hypertension. Sodium sensitivity is an independent cardiovascular risk factor in Japanese patients with essential hypertension.

Cardiovascular complications in patients with primary aldosteronism

Primary aldosteronism (PA) is widely believed to be a relatively benign form of hypertension associated with a low incidence of vascular complications. However, several recent studies showed that cardiovascular complications were not rare in PA. PA is known as one of the most typical forms of sodium-sensitive hypertension. Recently, we found that the sodium sensitivity of blood pressure was a marker for greater risk for cardiovascular complications, especially stroke, in patients with essential hypertension. Therefore, we investigated cardiovascular complications in 58 patients with PA confirmed to be Conns adenoma. Cardiovascular complications were found in 34% of 58 patients. Coronary artery disease was found in only one patient (1.7%), as angina pectoris. Stroke was found in nine patients (15.5%), four patients (6.9%) with cerebral infarctions and five patients (8.6%) with cerebral hemorrhages. Proteinuria and renal insufficiency were found in 14 (24.1%) and 4 (6.9%) patients, respectively. The incidence of cerebral infarction and renal insufficiency was greater in men than women. The prevalence of proteinuria was greater in patients with than without stroke (P = 0.03) among those aged older than 40 years. These results indicated that cardiovascular complications, especially stroke and proteinuria, were common in patients with PA, and proteinuria might be an indicator for stroke as target-organ damage.

Prevalence of Renal Artery Stenosis in Autopsy Patients With Stroke

BACKGROUND AND PURPOSE Atherosclerotic renal artery stenosis commonly exists as one manifestation of more generalized atherosclerosis. It is a progressive but potentially curable disorder. Thus, information on renal artery involvement in atherosclerotic diseases could be important. We investigated the prevalence of renal artery stenosis in autopsied patients with stroke over 40 years of age. METHODS From 2167 consecutive autopsy patients who died between 1980 and 1997, we studied 346 cases of mean age of 69+/-11 years with clinical evidence of stroke. RESULTS Atherosclerotic renal artery stenosis (>/=75% luminal area narrowing) was found in 36 patients (10.4%). Patients with renal artery stenosis were older and had worse renal function. Renal artery stenosis was found in 14.7%, 28.6%, and 23.9% of patients with hypertension, renal insufficiency, and aortic aneurysm, respectively. Extracranial carotid artery stenosis (>50% luminal area narrowing) was found in 101 patients (29.2%). Of the 346 stroke patients, 256 had a history of brain infarction. In patients with brain infarction, renal artery stenosis was found in 31 (12.1%) and carotid stenosis was found in 81 (33.6%). Patients with carotid artery stenosis were more likely to have renal artery stenosis than patients without carotid artery stenosis (24.4% versus 5.9%, P<0.0001). Multiple logistic regression analysis identified renal insufficiency, hypertension, female gender, and presence of carotid artery stenosis as independent predictors of renal artery stenosis in patients with brain infarction. CONCLUSIONS These data reveal that atherosclerotic renal artery stenosis is common in patients with stroke, especially in those with brain infarction.

Circadian rhythm of natriuresis is disturbed in nondipper type of essential hypertension

We examined the circadian rhythm of urinary sodium excretion and the effects of sodium restriction on rhythm in both dipper and nondipper types of essential hypertension. Patients (n = 26) with essential hypertension were maintained on relatively high- (10 to 12 g/d of sodium chloride) and low-sodium (1 to 3 g/d) diets for 1 week each. On the last day of each diet, 24-hour blood pressures (BPs) were measured every 30 minutes noninvasively with an automatic device, and on the last 3 days, urinary samples were collected for both daytime (7:00 AM to 9:30 PM) and nighttime (9:30 PM to 7:00 AM). Eight patients were classified as dippers based on a more than 10% reduction in mean arterial pressure (MAP) from daytime to nighttime on a high-sodium diet, and 18 patients were classified as nondippers. A nocturnal decrease in urinary sodium excretion rate (U(Na)V) on the high-sodium diet was observed in dippers (from 7.5 +/- 2.1 during the day to 5.3 +/- 2.5 mmol/h at night; P < 0.0001), but not in nondippers (6.7 +/- 2.1 v 7.6 +/- 2.3 mmol/h; not significant). In nondippers, the night-day ratio of sodium excretion was significantly reduced from 1.2 +/- 0.4 to 0.8 +/- 0.3 (P < 0.003) by sodium restriction; at the same time, the night-day ratio of MAP was reduced from 0.98 +/- 0.04 to 0.93 +/- 0.05 (P < 0.05). In dippers, the night-day ratios of MAP and U(Na)V were not affected by sodium restriction, and both ratios remained constant at less than 1. Before sodium restriction, the night-day ratio of sodium excretion correlated with that of MAP (r = 0.78; P < 0.0001), whereas there was no significant correlation (r = -0.05) after sodium restriction. These findings showed that the circadian rhythm of renal sodium excretion differed between the two types of essential hypertension. The enhanced nocturnal natriuresis and diminished nocturnal BP fall on a high-sodium diet, recognized in nondippers, were both normalized by sodium restriction, resulting in circadian rhythms with nocturnal dips in U(Na)V and BP.

Changes in the circadian rhythm of blood pressure in primary aldosteronism in response to dietary sodium restriction and adrenalectomy

Objective Recently, we found that sodium restriction restored the circadian rhythm of blood pressure from non-dippers to dippers in patients with a sodium-sensitive type of essential hypertension. In the present study, we investigated the effects of sodium restriction on the circadian blood pressure rhythm in patients with primary aldosteronism, a typical sodium-sensitive form of secondary hypertension. Design and methods We performed 24 h blood pressure monitoring in eight patients with primary aldosteronism due to unilateral adenoma (Conns syndrome) during normal-sodium (7–12 g/day of NaCl) and low-sodium (1–3 g/day) diets, and after adrenalectomy. Results Sodium restriction lowered the 24 h mean arterial pressure from 116 ± 14 to 109 ± 12 mmHg (P < 0.01). During a normal-sodium diet, there was no change in systolic, diastolic and mean arterial pressures during the night-time compared with the daytime. In contrast, during a low-sodium diet, all night-time pressure values were significantly lower than those in the daytime. After adrenalectomy, the night-time pressures in patients on a normal-sodium diet were lower than those of the daytime. The nocturnal mean arterial pressure fall was increased by sodium restriction and adrenalectomy. Conclusions These results indicate that the circadian rhythm of blood pressure was disturbed in patients with primary aldosteronism who maintained a relatively high sodium intake. Both adrenalectomy and sodium restriction restored a nocturnal dip in blood pressure in primary aldosteronism. Therefore, sodium restriction affects the circadian blood pressure rhythm in sodium-sensitive types of hypertension, not only in primary hypertension, but also in secondary hypertension.

Determinants of circadian blood pressure rhythm in essential hypertension

It has been postulated that the lack of nocturnal blood pressure fall in patients called nondippers is associated with more serious end organ damages by hypertension than in dippers whose blood pressure falls during the night. Recently, we found that sodium restriction shifted circadian rhythm of blood pressure from that of a nondipper to a dipper in patients with essential hypertension. In the present study, we aimed to clarify these important findings from the different approaches, and examined which factors affected the diurnal rhythm of blood pressure. A total of 70 patients with essential hypertension were maintained on high and low sodium diets for 1 week each. Nocturnal fall in mean arterial pressure was calculated in each patient, and, based on multiple regression analysis, independent factors affecting this nocturnal fall were examined. Thirty-eight patients were classified as non-sodium-sensitive, whereas 32 were considered sodium sensitive, based on a >10% change in 24-h mean arterial pressure by sodium restriction. In all 70 patients, sodium sensitivity of blood pressure, as well as an interaction between sodium sensitivity and sodium restriction, were identified as independent factors affecting the nocturnal fall. In sodium-sensitive types, in addition to sodium restriction, glomerular filtration rate was identified, whereas, in non-sodium sensitive types, there was no significant factor. Based on multiple regression analysis, the present study reached the same important conclusion as our previous findings: namely, that the enhanced sodium sensitivity was an independent determinant for the diminished nocturnal fall in essential hypertension and that sodium restriction could restore the nocturnal decline, especially in patients with enhanced sodium sensitivity whose nocturnal decline was diminished. Reduced renal sodium excretory capability may be one of the mechanisms involved in nondipping.

A light-emitting diode light source for imaging of neural activities with voltage-sensitive dyes

We tested the possibility of using a high-power monochromatic InGaN light-emitting diode (LED) as an excitation light source for real-time optical imaging using the voltage-sensitive dye RH-795. Driven with a custom-designed, non-feedback-controlled constant-current circuit, the LED generated stable light with rapid on/off. The LED was comparable with commonly used halogen lamps in exciting RH-795. Acoustically evoked responses in the auditory cortex recorded with the two light sources were highly similar. Our results thus suggest that a high-power LED can be successfully used as an excitation light source for voltage-sensitive dyes, without the need of optical filters and shutters.

Identification and characterization of an insular auditory field in mice

We used voltage‐sensitive‐dye‐based imaging techniques to identify and characterize the insular auditory field (IAF) in mice. Previous research has identified five auditory fields in the mouse auditory cortex, including the primary field and the anterior auditory field. This study confirmed the existence of the primary field and anterior auditory field by examining the tonotopy in each field. Further, we identified a previously unreported IAF located rostral to known auditory fields. Pure tone evoked responses in the IAF exhibited the shortest latency among all auditory fields at lower frequencies. A rostroventral to dorsocaudal frequency gradient was consistently observed in the IAF in all animals examined. Neither the response amplitude nor the response duration changed with frequency in the IAF, but the area of activation exhibited a significant increase with decreasing tone frequency. Taken together, the current results indicate the existence of an IAF in mice, with characteristics suggesting a role in the rapid detection of lower frequency components of incoming sound.

Disturbed Circadian Rhythm of Urinary Albumin Excretion in Non-Dipper Type of Essential Hypertension

Recently, we found that the circadian rhythms of natriuresis as well as of glomerular filtration rate were disturbed similar to the blood pressure in non-dipper type of essential hypertension during intake of a high-sodium diet. In this study, we examined circadian rhythms of the urinary albumin excretion rate (AER), which is recognized as a marker of glomerular capillary hydraulic pressure, in addition to those of urinary sodium excretion and blood pressure in 27 patients with essential hypertension. The patients were maintained on relatively high (10–12 g) on low (1–3 g) sodium (NaCl) diets for 1 week. On the last day of each diet, the 24-hour blood pressure was measured every 30 min noninvasively, and during the last 3 days, urine samples were collected for determination of both daytime (07:00–21.30 h) and nighttime (21.30–07.00 h) sodium and AER variations. During the high-sodium diet, nocturnal falls in urinary sodium excretion and blood pressure were observed in dippers (n = 7), while they were not observed in non-dipper (n = 20). The nocturnal decline in AER was also observed in dippers (day: 37 ×/÷ 6 µg/min vs. night: 22 ×/÷ 5 µg/min; p < 0.02), while it was not observed in non-dippers (day: 49 ×/÷ 6 µg/min vs. night: 40 ×/÷ 8 µg/min; NS). During intake of the low-sodium diet, on the other hand, a nocturnal decline in AER was observed in both types of hypertension. Sodium restriction significantly reduced only the nighttime AER in non-dippers (p < 0.01). These findings indicate that changes in dietary sodium intake modified the circadian rhythms of both blood pressure and AER in non-dippers. Renal sodium handling may contribute to determining the circadian rhythm of blood pressure, and furthermore an elevated glomerular capillary hydraulic pressure during the night may enhance the nocturnal albumin excretion in non-dippers.

Deficiency of sphingomyelin synthase‐1 but not sphingomyelin synthase‐2 causes hearing impairments in mice

•  Sphingomyelin (SM) is a structural component of plasma membrane and may participate in signal transduction. The role of SM metabolism in hearing remains controversial. •  Here we examined hearing in mice deficient of SM synthase‐1 (SMS1) or SMS2, and show that only deficiency of SMS1 causes hearing loss. •  The hearing loss in SMS1 knockout mice is attributable at least in part to a reduction of endocochlear potential. •  The reduction of endocochlear potential is attributable at least in part to atrophy of the cochlear stria vascularis and its altered expression of K+ channels. •  Our results establish that SMS1 is essential for normal inner ear function.